In this new project, our major focus is to understand how cholesterol and cell surface receptors involved in lipoprotein metabolism function together to transmit signals from the cell surface to the cell interior. The receptors of interest belong to the LDL receptor (LDLR) gene family. We plan to use knockout, knockin, and transgenic methods to investigate how these receptors transmit signals from the cell surface to the cell interior, particularly in neuronal tissues. The site for activation of these receptors is likely to involve caveolae, a cholesterol-rich compartment of the plasma membrane that houses many of the putative downstream intermediates in LDLR family signaling. A major objective will be to determine if LDLR gene family members become activated in caveolae and to explore the possibility that caveolae cholesterol regulates their function. Inasmuch as tyrosine kinases are involved in LDLR family signal transduction and inasmuch as the structure and function of caveolae depend crucially on cholesterol, we will also investigate the role that cholesterol plays in compartmentalizing receptor tyrosine kinases in caveolae and how this sterol links kinase activity to multiple signaling pathways. Finally, we will study the function of caveolin-1, the major cholesterol binding protein in caveolae, and determine its role in maintaining the proper cholesterol level of caveolae.